Process for synthesizing semisynthetic penicillins using n-hydroxy succinimide mono-and dichloroacetate esters



United States Patent ABSTRACT OF THE DISCLOSURE Process for themanufacture of a compound having the general formula R -OOiNH--Rcomprising reacting a compound of the general formula with a compoundhaving the following general formula:

Rz-COOH Reaction occurs in an inorganic solvent at room temperature orbelow, The succinimide ester product which is formed is reacted with acompound of the following general formula:

to yield the product. The second reaction occurs in an inert organicsolvent atroom temperature or below. :The generic moieties shown arefully defined in the specification. The compound produced finds utilityin the pharmaceutical field.

This invention relates to a process for the manufacture of acid amides.It particularly relates to the process for the production of thecompound having the acid amide linkage, said compound having the generalformula:

ice

It has been proposed previously to produce aforementioned compoundshaving the general Formula I, especially to produce peptide compounds.As examples of the process for the production of the said compounds,there may be mentioned, for example, a method of using p-nitrophenylesters of acyl amino acids [M. Bodansz-ky, Ann. NY. Acad. Sci., 88 655(1960)], N-hydroxyphthalimide method [6. H. L. Nefkens, et al., J. Chem.Soc., 83, 1263 (1961)], and Andersons method [6. W. Anderson, et al.: J.Am. Chem. Soc.; 86(9), 1939 (1964)] according to which an amino acid,protected in its amino group, is reacted with N-hydroxysuccinimide inthe preswherein R stands for a member selected from the group consistingof alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, aralkyl, arylalkenyland heterocyclic carboxyl group; these radicals hereinbefore defined aresubsituted or unsubstituted by at least a member selected from the groupconsisting of halogen, nitro, nitroso, amino, imino, amidino, hydroxy,cycloalkyl, alkoxy, aryloxy, alkoxycarbonyl, alkylcarbonyl,arylcarbonyl, alkylamide, arylamide, alkylthio, alkenyl, cycloalkenyl,alkenylthio, alkenylcarbonyl, aryl, aralkyl, arylalkenyl andheterocyclic group; and R stands for a member selected from the groupconsisting of alkyl, cycloalkyl, aryl, aral kyl, amino, alkylamino,cycloalkylamino, arylamino aralkylamino, alkylamide, cycloalkylamide,alkenylamide, arylamide, aralkylamide, cyclohexylcarboxyarnide andcyclohexylamino group; these radicals are substituted or unsubstitutedby at least a member selected from the group consisting of halogen,nitro, alkyl, alkoxy, carboxy, alkylcarbonyl, al-kylamino, alkylamide,cycloalkyl, alkoxycarbonyl, cycloalkylamine, cycloalkylcarbonyl,cycloalkylamide, alkenyl, cycloalkenyl, alkenylcarbonyl,alkenylamino,"alkenylamide, aryl, aralkyl, arylalkenyl, arylamino,arylamide, arylcarbonyl, aralkylcarbonyl, aralkylamino, aralkylamide andheterocyclic group.

ence of dicyclohexyl carbodimide as a dehydrating agent to a succinimideester:

CO- H2 which was then reacted with amino acid to the peptide compound.Among others is known a method by Sa-kakibara et a1. [Bull. Chem. Soc.Japan, 38, 1979 (1965)]. According to this method, trifluoroacetic acidanhydride was reacted with N-hydroxysuccinimide to give the ester, i.e.trifluoroacetoxysuccinimide, being followed by a synthesis to providethe aforementioned succinimide ester, which was then reacted furtherwith amino acid to the peptide compound.

This last mentioned prior process has a number of grave disadvantages,including that the intermediate product or trifiuoroacetoxysuccinimideis almost impossible to crystallize and further that this compound andthe starting material, the latter being highly poisonous trifluoroaceticacid, are substantially difficult to handle. Also these substances arehighly expensive.

The main object of this invention is to provide a process for theproduction of the compound having acid amide linkage which is useful fora physiologically active agent such as pharmaceuticals and the like.

It is another object of the present invention to provide a process ofthe above kind, capable of obviating the above mentioned various andgrave disadvantages.

In order to realize the above objectives, the process according to theinvention in its broadest aspect comprises: reacting a compound having ageneral formula:

R1COON CO Hz wherein R stands for a member selected from the groupconsisting of hydrogen, monochloroloweralkyl and dichloroloweralkylgroup, with a compound having the following general formula:

Rg-COOH wherein R has the same meaning as set forth hereinbefore, toprovide the succinimide ester compound having the general formula:

Rz-COON CO-- H:

wherein R has the meaning set forth above, and subsequently reacting thesaid succinimide compound with a compound of the following generalformula:

wherein R has the same meaning as set forth hereinbefore, thereby toprepare the desired product expressed in the general Formula 1.

Comparing with these conventional methods, the process according to thepresent invention provides a number of industrial advantages; i.e.,succinimide esters as expressed in the general formula:

CO-GH:

are easily synthesized from N-hydroxysuccinimide esters of the generalformula:

CO-Glh wherein R and R have respective same meanings as before.

The starting material usable in the novel process is easy to treat,neither hazardous nor expensive.

There is also no necessity for specifically separating the intermediatesuccinimide ester from reaction mixture, so that the above mentionedcompound: R NH can be added directly thereto, for obtaining the saidfinal compound having the acid amide linkage.

The compound set forth hereinabove, represented by general Formula III,such as formate ester of N-hydroxy succinimide, monochlorofatty acidester of N-hydroxy succinimide or dichlorofatty acid ester of N-hydroxysuccinimide may be used as starting materials. Each of these materialsmay be prepared by conventional processes, or alternatively by the novelprocess as disclosed herein.

For carrying out the invention, the process can be carried into effect,for instance, in such a way that an ether solution of formic,monochlorofatty or dichlorofatty acid is partially or completelysaturated with ketene to prepare a mixed anhydride of acetic acid-formicacid, -monochlorofatty acid or -dichlorofatty acid, which is thenreacted with N-hydroxy succinimide to prepare the starting material.Ordinarily the said N-hydroxy suc- 4 chlorofatty acid ester or N-hydroxysuccinimide-dichlorofatty acid ester produced by the aforementionedprocess may be used even in their crude form, non-recrystallized.

The reaction between the said N-hydroxy succinimide ester (III) and thesaid compound: R COOH (IV) may be conducted, preferably in an inertorganic solvent, such as tetrahydrofuran, dimethylformamide or the like.'It may be preferable that the reaction is carried out in the presenceof a basic organic solvent e.g., a tertiary amine such astrimethylamine, triethylamine, pyridine or the like. Also the reactionmay be conducted at a roomor a reduced-temperature, as may be required.Succinimide esters as expressed by general Formula II resulting from thereaction between the said compound ,(III) and the said compound (IV) areseparated therefrom and of course can be used in the next followingreaction step. It is not always necessary, however, to isolate thecompound (II), and so aforementioned compound (I) having the acid amidelinkage may be obtained without any separating step and thus by reactingthe said reaction mixture of the said compound (IV) directly with thecompound expressed generally as R -NH Further it is of course necessaryto protect or block the radicals ,R and R in aforementioned compounds,if such radicals should be decomposed or affected by undesired change.Amino, hydroxy and the like radicals may be mentioned in this case.

The compound (IV) prepared by the series of the reaction steps may beextracted if desired at controlled pH with a suitable organic solventsuch as ethyl acetate, methyl isobutyl ketone or the like. Besides itmay be recovered by various conventional processes which are commonlyemployed in the separation of organic compounds, such as drying-up invacuo, crystallization from solvents, chromatographic processing and thelike technique.

Examples of compounds which correspond to Formulas III and IV and theirreaction product succinimide ester (II), forming part of the instantinvention, are

cinimide-formate ester, N-hydroxy succinimide-mono- 40 listed in thefollowingTablel:

TAB LE 1 Compound (III) Compound (IV) Compound (II) CO-ClIz COCIl2R1COO-N R2-COOII R:COON

(JO-CH: CO-(JH:

succinimide Acetic acid N-acctoxysuccinimidc.

Acrylic acid.

Crotonic acid... Cyclohexanccarboxy B-cyclohcxylacrylic acidCarbobcnzoxyglycinc. Carbobcuzoxyvalinc.

Plienylacctic acid.

2-ctl1oxy-1-naphtlioic acid. Tliiophcn e-Zacetic acid.zx-Mcthylphcnoxyacctic aci Acrylic acid Crotonic acidCyclohcxauccarboxylic acid. fi-cyclolicxylacrylic acid.Carbobcnzoxyglycine...

...... Phcnylacctic acid Capric acid"... Stcaric acid... Cinnamic acid..

acid.

.......... Carbobcnzoxy-L-plicnylalanlne. Carbobcnzoxy-Dphenylglycine.a-l\lcthoxyisol utyric acid.

........ a-h'Iethoxy-3,4-dichloropl 3 a-Ethyl-phcnoxyacctic acid.

...... 2,4-dicl1loroplicnoxyacctic acid p-Chlorophenylacctic acid...

. B-5-nitro-2-t'u1'luryl acrylic acid Acetic acid Carbobcnzoxyvalinc.

.. Carbobenzoxy-D-phcnylglycinc a-Mcthoxyisobutyric acid.

..... N-acrylyloxysuccinimidc.

.. N-crotonyloxysuccinimide.

Ncyclohexanoyloxysuccinimidc.

.... N-B-cyclohcxylacrylyloxysuccinimide.

N-carbobcnzoxyglycyloxysuccinimidc.

.... N-carbobcnzoxyvalyloxysuccinimidc.

....... N-carbobcnzoxy-L-phcnylalanyloxysuccinimidc.N-carb0benzoxy-D-phcnylglycyloxysuccinimidc.N-a-mctlioxyisobutyloxysuceinimide.

....... N-phcnylacctoxysucciuimide.

..... N-capryloxy-succinimidc.

N-stcaryloxysucciuimidc.

N-cinnamoyloxysuccinimidc.

. N-isonicotiuoyloxysuccinimidc.

. N-bcnzoyloxysuccinimidc.

. N-carbobcnzoxy-L-lcucyloxysuccinilnitlc.

N-phenoxyacctoxysuecinimidc.

d. N-a-mcthoxy-3A-dichlorophcynlacetoxysucciuiniidc.

... N-u-etliyl-phcnoxyacctoxysuccinimidc.

N-2-cthoxy-l-naphthoyloxysuccinirnidc.

..... N-thiophenc-2-acctoxysuccinimide.

... N-a-mcthyl-phcnoxyacetoxysuccinimidc.

... N-2,4-dichlorophcnoxyacctoxysuccinimide.

... N-p-chlorophcnylacetoxysuccinimidc.

... N-p-mcthylbcnzoyloxysuccinimidc.

. N-Z-naphthoyloxysuccinimidc.

N B-5-nitro-2-furiurlyacrylyloxysucciniiuidc.

... N-acctoxysucciniiuidc.

. N-acrylyloxysuccinimide.

... N-crotonyloxysuccinimidc.

. N-cycloliexanoyloxysuccinimidc.

... N-B-cyclohcxylacrylyloxysuccinimidc.

... N-carbobcnzoxyglycyloxysuccinimidc.

. N-carbobcnzoxyvalyloxysuccinimidc.

. N-carbobcnzoxy-D-phcnylglycyloxysucciuiiuidc.N-a-mctlwxyisobutyloxysucciniinidc.

N-phenylacctoxysuccinimidc.

.-. N-capryloxysuccinimidc.

. N-stcaryloxysuccinimidc.

. N-cinnamoyloxysuccinimidc.

D0 Isonicotiuic acid N-isonic0tiu0yloxysucciuimidc.

TABLE 1C0n'tinued Compound (IV) ..I Z-ethoxy-l-naphthoic acid-Thiophene-Z-acetic acid. a-Methylphenoxyacetic aci p-Methylbenzoic acid.2-naphthoic acid Acetic acid Acrylic acid. Crotonic acidCyclohexauecarboxylic acid. fl-Cyclohexylac'rylic acid Carbobenzoxyglycinc. Oarbobenzoxyvaline.

Carbobenzoxy-D-phenyl a-Methoxyisobutyric acid Phenylacetic acid. Capricacid Stearic acid Cinnamic acid.

Isonicotinic acid B cnzoic acid Do N-aiLSIIOROChIOI'OPIOPlOIIYIsuccmimide- Z-ethoxy-l-naphthoic acid Thiophene-2-aceticacida-Methylphcnoxyacetic acid. 2,4-dichlorophenoxyacetic acip-Ohlorophenylacctic acid-.. p-Methylbenzoic acid..--

Z-naphthoic acid fl-5-nitro-2-iurfuryl acrylic aci Acetic acid Acrylicacid. Orotonic acid- Cyclohexanecarboxyhc acid. B-cyclohexylacrylicacid. Carbobenzoxyglycine.

Carbob enzoxyvaliue a-Methoxyisobutyric acid Phenylacetic acid Capricacid. Stearic acid Cinnamic acid Isonicotinic acid. B enzoic acidCarbobenzoxy-L-leucine Thiophene-Z-acetic acid p-Methylbenzoic acid....Z-naphthoic acid Benzoic acid.-. Carbobenzoxy-L-phenylalanine.

.......... Carbobenzoxy-L-leucine--..-- Phenoxyacetic acid..-........

a-Methoxy-3,4-dichlorphenyl-acctic aei a-Ethyl-phenoxyacetic acid.

p-Chlorophenylaeetic acid....

fi--nitro-2-turiuryl acrylic acid.

Garbobenzoxy-L-phenylalanrne Carbobenzoxy-L-leucine. Phenoxyacetie acida-Methoxy-3, 4-dichlorophenylacetic acid. a-E thyl-pheuoxyacetic acidCarbobenzoxy-L-pheriylalanine Phenoxyacetic acid a-Methoxy-ii,4-dichlorophenylac a-Ethyl-phenoxyacetic acid 2-ethoxy-1-naphthoic acid.

a-Methylphenoxyacetic acid.. 2,4-dichlorophenoxyacctic acid.p-Chlorophenylacetic acid...-

. N-benzoyloxysuccinimidc.

N-carbobcnzoxy-L-phenylalanyloxysuccinimide.

. N-carbobenzoxy-L-lcucyloxysuccinimidc.

N-phenoxyacctoxysuccinimide.

. N-a-methoxy-3,4-dichlo1'ophenylacetoxysuccinimide.

............... N-m-ethyl-phenoxyacetoxysuceinimide.

............. N-2-ethoxy-l-naphthoyloxysuccinimide.N-thiophene-2-acetoxysuccinimide.

N-wmethyLphenoxyacetoxysuccinimide. 2, 4-dichl0r0phen0xyacetic acidN-2,4-dichlorophenoxyacetoxysuccinimide.

............. N-p-chlorophcny1acctoxysuccinimide.

............. N-p-methylbenzoyloxysuccinimidc.

......... N-2-naphthoyloxysuccinimide.

. N -B-5-nitro-2-furfury1 acrylyloxysuccinimidc.

. N-acetoxysuccinimide.

. N -acrylyloxysuccinimide.

....... N-crotonyloxysuccinimide.

......... N-cyclohexanoyloxysuceinimide.

......... N-fl-cyclohexylacrylyloxysuccinimide.

. N-carbobenzoxyglycyloxysuccinimide.

. N-carbobenzoxyvalyloxysuccinimide.

N-carbob enzoxy-D-phenylglyeyloxysuccinimide.N-a-methoxyisobutyloxysuccinimide.

. N-phenylacetoxysuccinimide.

-.. N-capryloxysuccinimide.

-.. N-stearyloxysuccinimidc.

- N-cinnamoyloxysuccinimide.

..... N-isonicotinoyloxysuccinimidc.

.. N-benzoyloxysuccinimide.

. N-carb ob enzoxy-L-phenylalanyloxysuccinimide.

. N-carbob enzoxy-L-leucyloxysuccinimide.

..- N-phen0xyacetoxysuccinimidc.

... N-a-mcthoxy-B,4-dichlorophenylacetoxysuccinimidc.N-a-ethyl-phcnoxyacetoxysuccinimide.

. N-2-ethoxy-l-naphthoyloxysuccinimide.

. N-thi0phene-2-acetoxysuccinimide.

. N-a-methyl-phcnoxyacetoxysuccinimidc.

- N-2,4-dichlorophenoxyacetoxysuccinimidc.

. N-p-chlorophenylacetoxysuecinimide.

. N-p-methylbenzoyloxysuccinimidc.

. N-2-naphthoyloxysuccinimidc.

.-- N-6-5-nitr0-2-furfuryl acrylyloxysuccinimide.

. N-acetoxysuccinimide.

. N-acrylyloxysuccinimide.

. N-crotonyloxysuccinimide.

..... N-cyclohexanolyloxysuccinimide:

....... N-fl-cyelohexylacrylyloxysuccinimide.

....... N-carb0beuzoxyglycyloxysuccinimide.

....... N-carb0benzoxyvalyloxysuccinimide.

....... Ncarbobenzoxy-D-phcnylglycyloxvsuccinimide.N-a-methoxyisobutyloxysuccinimidc.

..... N-phenylacetoxysuceinimide.

..... N.capryloxysuccinimide.

-.- N-stearyloxysuccinimide.

-.. N-cinnamoyloxysuccinimidc.

. N-isonicotinoyloxysuccinhnide.

N-benzoyloxysuccinimide.

. N-carbobenzoxy-L-phenylalanyloxysuccinimide.N-carbobenzoxy-L-leucyloxysuccinimide.

N-phenoxyacetoxysuccinimide.

. N-a-methoxy-3,4-dichlorophenylacetoxysuccinimidc. N--ethyl-phen0xyacetoxysuccinimide.

- N ethoxy-Lnaphthoyloxysuccinimide.

N-thiophene-2-acetoxysuccinimide.

. N-a-mcthyl-phenoxyacetoxysuccinimidc.

. N-2,4-dichlor0phenoxyacctoxysuccinimide.

. N-p-chlcr0phcnylacetoxysuccinimide,

. N-pmethylbenzoyloxysuccinimide.

, N-Z-naphthoyloxysuccinimide.

Do fl-5-nitro-2-furfuryl acrylic acid-N-B-5-nitro-2-iurfurylacrylyloxysuccinimide.

The following preparations illustrate several modes of preparaingsuccinimide ester (11) in the present invention.

PREPARATION 1 N-acetoxysuccinimide Yield: 0.4 g. (recovery: 51%). M.P.:found: 131-133? C. reference: 130 C.

Elemental analysis-Found (percent): C, 45.99; H, 4.63; N, 8.96.Theoretical as based upon C H NO (percent): C, 45.86; H, 4.49; N, 8.91.

PREPARATION 2 N-carbobenzoxyglycyloxysuccinimide 2 ml. oftetrahydrofuran were added to a mixture of 1.05 g. ofcarbobenzoxyglycine (5 mmole) and 2.26 g. of

N-dichloroacetoxysuccinimide (10 mmole). To this solution 1 ml. oftriethylamine was added with stirring. The mixture was stirred for afurther 1 hour at room temperature. After finishing the reaction, waterwas added, cooled, 75. then filtered, and solid material recovered waswashed with water. This material was dissolved in methylene chloride,and dried with anhydrous sodium sulfate. After removal of the dryingagent by filtration, an addition of diethylether resulted in theprecipitation of N-carbobenzoxyglycyloxysuccinimide as crystals.

Yield: 1.10 g. (recovery: 73%). M.P.: found: 115 C. references: 114 C.

Elemental analysis-Found (percent): C, 54.95; H, 4.65; N, 9.31.Theoretical as based upon C H N O (percent): C, 54.90; H, 4.57; N, 9.15.

PREPARATION 3 N-carbobcnzoxyglycyloxysuccinimide To a solution of 1.05g. of carbobenzoxyglycine mmole) and 2 g. ofN-monochloroacetoxysuccinimide (ca. mmole) in 1 ml. of tetrahydrofuranwas added dropwise 1 ml. of trimethylamine (7.2 mmole) with stirring Thereaction was allowed to continue for 2 hours. Following the reaction,the precipitated reaction product was filtered after addition of 25 ml.of water under cooling, then washed with water. The precipitatedmaterial was recrystallized from ethanol-ether mixture, yieldingN-carbobenzoxyglycyloxysuccinirnide as white crystals.

Yield: 750 mg. (recovery: 49%). M.P.: Found: 112.5 113.5 C. reference:113114 C.

PREPARATION 4 N-carbobenzoxyglycyloxysuccinimide The triethylamine inPreparation 3, was replaced by pyridine to produceN-carbobenzoxyglycyloxysuccinimide as white crystals.

Yield: 342 mg. (recovery: 23%). M.P.: Ill-113 C.

PREPARATION 5 8.4 ml. of triethylamine (60 mmole) were added dropwise toa cooled, stirred solution of 4.08 g. of phenylacetic acid (30 mmole)and 10.2 g. of N-dichloroacetoxysuccinimide (45 mmole) in 6 ml. ofdimethylformamide. The solution was stirred for about 2 hours and thenan excess amount of water was added. The reaction mixture was thenallowed to stand overnight. After cooling the thus precipitated crystalswere separated by filtration, Washed with water repeatedly, yielding5.55 g. of crude crystals of N-phenylacetoxysuccinimide (recovery: 79%which was recrystallized as colorless crystals from ethyl ether.

Yield: 4.15 g. (recovery: 60%). M.P.: 118119 C.

Elemental analysis-Found (percent): C, 62.08; H, 4.85; N, 5.92.Theoretical as based upon C H NO (percent): C, 61.80; H, 4.76; N, 6.01.

PREPARATION 6 N-capryloxysuccinimide 1.05 ml. of triethylamine wereadded dropwise with stirring to a cooled solution of 0.86 g. of n-capricacid (5 mmole) and 1.7 g. of N-dichloroacetoxysuccinimide (7.5 mmole) in2 ml. of dimethylformamide. The mixture was then stirred in an ice bathfor about one hour, and then 15 ml. chilled water was added. Thereaction mixture was then cooled and the precipitated crystals wereseparated. This precipitated material was recrystallized from isopropylalcohol-ethyl acetate mixture.

Yield: 500 mg. (recovery: 37%). M.P.: 5961 C.

Elemental analysis.Found (percent): C, 62.90; H, 9.10; N, 5.28.Theoretical as based upon C H NO (percent): C, 62.44; H, 8.61; N, 5.20.

PREPARATION 7 N-carbobcnzoxy-L-phenylalanyloxysuccinimide 1.05 ml. oftriethylamine were added dropwise with cooling to a mixture of 1.2 g. ofcarbobenzoxy-L-phenylalanine (4 mmole) and 1.36 g. ofN-dichloroacetoxysuccinimide (6 mmole) in 2 ml. of dimethylformamide.The mixture was stirred with cooling, followed by addition of 15 ml. ofwater, then the sedimented crystals were separated therefrom.N-carbobenzoxy-L-phenylalanyloxysuccinimide was recrystallized fromisopropyl alcohol.

Yield: 670 mg. (recovery: 42%). M.P.: 133 C.

PREPARATION 8 N-stearyloxysuccinimide 1.05 ml. of triethylamine wereadded dropwise to a cooled, stirred mixture of 1.42 g. of stearic acid(5 mmole) and 1.7 g. of N-dichloroacetoxysuccinimide (7.5 mmole) in 6ml. of dimethylformamide. The solution was stirred for about 1 hour withcooling, and then added with 24 ml. of water. The precipitated crystalsof N- stearyloxysuccinimide were separated, which were finallyrecrystallized from isopropyl alcohol.

Yield: 1.16 g. (recovery: 61%). M.P.: 8890 C.

Elemental analysis.Found (percent): C, 69.62; H, 10.82; N, 3.94.Theoretical as based upon C H NO (percent): C, 69.25; H, 10.30; N, 3.67.

PREPARATION 9 N-cinnamoyloxysuccinimide 1.43 ml. of triethylamine wereadded to a mixture of 0.7 g. of cinnamic acid (5 mmole) and 1.7 g. ofN-dichloroacetoxysuccinimide (7.5 mmole) in 2 ml. of dimethylformamide,stirring for about 1 hour, followed by addition of 10 ml. of water. Thesolution was neutralized with 1 N-HCl and cooled, thereby separating thesedimented crystals and washed with water. The precipitated material wasrecrystallized from isopropyl alcohol-ethyl acetate.

Yield: 450 mg. (recovery: 37%). M.P.: 173-175 C.

Elemental analysis.Found (percent): C, 62.40; H, 4.29; N, 5.47.Theoretical as based upon C H NO (percent): C, 63.67; H, 4.53; N, 5.71.

PREPARATION 10 N-benzoyloxysuccinimide 1.05 ml. of triethylamine wereadded dropwise to a solution of 0.61 g. of benzoic acid (5 mmole) and1.7 g. of N-dichloroacetoxysuccinimide (7.5 mmole) in 2 ml. ofdimethylformamide. The solution was stirred for about 2 hours withcooling, adding 15 ml. of water, standing in an ice bath, and thenseparating the precipitated crystals of N-benzoyloxysuccinimide.

Yield: 500 mg. (recovery: 46%). M.P.: 133135 C.

Elemental analysis-Found (percent): C, 60.27; H, 4.19; N, 6.57.Theoretical as based upon C H NO (percent): C, 60.27; H, 4.14; N, 6.39.

PREPARATION 11 N-carbobenzoxy-D-phenyl glycyloxysuccinimide 1.05 ml. oftriethylamine were added dropwise with stirring to a cooled solution of1.43 g. of carbobenzoxy- D-phenylglycine (5 mmole) and 1.7 g. ofN-dichloroacetoxysuccinimide (7.5 mmole) in 2 ml. of dimethylformamide.The solution was then stirred for 2 hours in an ice bath, adding anequal volume of chilled water and then precipitated crystals thusseparated. The recrystallization was performed from isopropyl alcohol,thus obtained N-carbobenzoxy-D-phenylglycyloxysuccinimide as whiteneedle crystals.

Yield: 610 mg. (recovery: 32%). M.P.: 144l46 C.

Elemental analysis.Found (percent): C, 63.31; H, 4.86; N, 7.45.Theoretical as based upon C H N O (percent): C, 62.82; H, 4.75; N, 7.33.

Compounds, which are represented by Formula II, formula R NH andcompound having acid amide linkage as Formula I are shown in thefollowing Table 2.

TAB LE 2 Succinimide ester Compound (11) Compound having acid amidelinkage Rr-C O-ON I Compound (I) C OCHZ Ra-NHg R2-C ONHR3N-earbobenzoyglycloxysuceinimide Glycine ethyl esterCarbobenzoxyglyclyglycine ethyl ester.N-fi-carbobenzoxyaminovaleroyloxy-succinimide -Aminovaleric acid methylester o-Cargpblenztoxy aminovaleryl-a-aminovaleric acid me y es er.N-carbobenzoxy-L-phenylalanyloxy-succinimide Glycine ethyl esterCarbobenzoxy-L-phenylalanyl-glycine ethyl esterN-carbobenzoxy-lll-leucyloxy-succinimide do Carbobenzoxy-L-leueylglycineethyl ester.

Do L-phenylalanyl glycine ethyl ester-Cari?obenzoxy-L-leucyl-L-phenylalanyl-glycine ethyl es er. N-phenylaeetoxysueeinhnide fi aminopenioillanic acid Benzylpenicillin. N-a-ethyl-phenoxyacetoxysuccinimide .d Phenoxypropylpenicillin.

N-n-methoxy-3,-dichlorophonylacetoxyN-2-ethoxy-1-naphthoyloxysuccinimitle N-thi0phene-2-acetoxysuccinimideN-a-methyl-phenoxyacetoxysuccinim N-carbobenzoxy-D-phenylglyoyloxy-succ'N-acetoxysuccinimide o N -dichloroacetoxysuocinimide.N-propionyloxysuecinimide N-eyclohexanecarbonyloxysuccinhnide-N-phenylacetoxysuccinimide N -benzoyloxysuccinimideN-phsnylaeetoxysuccinimida. N-2,4-dichlorophenoxyaoetoxy-suooinimideNp-chlorophenylacetoxysuccinimida- N-p-methylbenzoyloxysuccinimideminocephalosporanic acid.

inopenicillanio acid p-Chloroaniline3,4-dichloro-a-methoxybenzylpenieillin. Z-ethoxy-l-naphthylpenicillin.Cephalotin.

Phenoxyethylpenicillin. a-Aminobenzylpenicillin. N-n-hexylacetamide.N-benzylacetamide. N-allylacetamide. N-Z-pyridylacetamide.N-5-nitro-2-thiazoly acetamide. N-phenylaminoacetamide.N-p-chlorophenyldichloroaoetamide. N-phenylpropionamide.N-cyclohexylcyclohexane carboxamide.

. N-benzylphenylacetamide.

N-p-methoxyphenylbenzamide. N-cyclohexylphenylacetamide.

N-3,4-dichlorophenyl-2,4-dichloro-phenoxyaeetamide.N-p-chlorophenyl-p-chlorophenylacetamide.N-p-methylphenyl-p-methylbenzamide.

N-Z-naphthoyloxysuccinimiden-Butylamine N-n-butyl-2-naphthamide.N-2-naphthoyloxysuccinimide. B-PhenylethylamineN-fl-phenylethy1-2-naphthamide. N-phonoxyaoetoxysuccinimide BenzylamineN-benzylphenoxyacetamide. N-aoryloyloxysuceinimide Isopropylamine N-isopropylaerylamide. N-isonicotinoyloxysuccinimide 2-aminothiazoleN-2-thiazolylisonicotlnamide.N-fl-5-nitro-2-furfurylaerylyloxy-succinimide Benzylamine N-benzyl-fl-5-nitro-2-furiurylacrylamide. N-phenylacetoxysuocinimide.Morpholine N-phenylacetylmorpholine. N-isonicotinoyloxysuceinimideIsopropylhydrazine N-isopropylaminoisonicotinamide.N-p-chlorophenoxyaeetoxysuccinimide PhenylhydrazineN-phenylamino-p-chlorophenoxyacetamide. N -acetoxysuccinimidep-Aminobenzoic acid ethyl ester--. N -p-ethoxycarbonylphenylacetamide. N-hippuropyloxysuccinimide Anilinem enzoylglycine anilide.N'(i-chloropropionyloxysucoinimide BenzylammeN-benzyl-B-ehloropropionamide.

The compounds produced by the claimed process are useful astherapeutical agents for the treatment of various types of bacterialinfections.

The following examples are set forth for purposes of illustration onlyand are not to be construed as limiting he scope of the invention.

EXAMPLE 1 Carbobenzoxyglycylglycine ethyl ester 1 ml. of triethylamine(7 mmole) was added dropwise to a cold solution of 1.05 g. ofcarbobenzoxyglycine (5 mmole) and 1.55 g. ofN-dichloroacetoxysuccinimide (7 mmole) in 3 ml. of dimethylformamide.After 2 hours 0.07 ml. of water was added, stirring for several minutes,and then a mixture of 0.7 g. of glycine ethyl ester hydrochloride (5mmole), 0.7 ml. of triethylarnine (5 mmole), 3 ml. of dimethylformamideand 0.55 ml. of water was added thereto. The reaction was allowed tocontinue for 1 hour with stirring. After adding ml. of chilled water,allowed to stand in an ice bath, the solution was extracted twice withethyl acetate. This ethyl acetate extract was combined with additionalethyl acetate extract and the combined extracts containing the productwere washed with 10% solution of sodium bicarbonate, 1 N-hydrochloricacid and water respectively, and dried over anhydrous sodium sulfate.After removal of the drying agent by filtration, the extract was driedup in vacuo. The residue was recrystallized from water containingethanol to obtain crystals of carbobenzoxyglycine ethyl ester.

Yield: 1.08 g. (recovery: 73%). M.P.: Found: 81- 80 C. reference: 808lC.

Elemental analysis-Found (percent): C, 57.30; H, 6.21; N, 9.54.Theoretical as based upon C H N O (percent): C, 57.21; H, 6.16; N, 9.52.

EXAMPLE 2 The procedure of Example 1 was again followed substantially inevery detail except that the dimethylform- EXAMPLE 3S-carbobenzoxyaminovaleryl aminovaleric acid methyl ester 1 ml. oftriethylamine was added dropwise with stirring to a cooled solution of1.26 g. of fi-carbobenzoxyaminovaleric acid (5 mmole) and 1.58 g. ofN-dichloroacetoxysuccinimide (7 mmole) in 3 m1. of dimethylformamide.The mixture was stirred in an ice bath for about 4 hours, followed by anaddition of 0.07 ml. of water, and then kept in cooled condition forfurther 40 minutes. Next, the mixed solution of 0.85 g. ofo-aminovaleric acid methylester hydrochloride (ca. 5 mmole), 0.7 m1 oftriethylamine (5 mmole) and 4 ml. of dimethylformamide were addedthereto with cooling, while stirring for-2.5 hours. The mixture wasallowed to stand overnight, then added with 30 ml. of water andextracted with ethyl acetate. The ethyl acetate extract was washed withsodium bicarbonate solution, diluted with hydrochloric acid and waterrespectively and dried over anhydrous sodium sulfate. After removal ofthe drying agent by filtration, the extract was condensed in vacuo. Thesedimented material was separated, washed with ether, dried in adesiccator, thus obtaining the product as white crystals.

Yield: 1.37 g. (recovery: 75%). M.P.: 9496 C.

Elemental anaylsis.-Found (percent): C, 62.87; H,

7.83; N, 7.80. Theoretical as based upon C H N O (percent): C, 62.62; H,7.74; N, 7.69.

EXAMPLE 4 Carbobenzoxy-L phenylalanylglycine ethyl ester 1.07 ml. oftriethylamine were added dropwise with cooling to a mixture of 1.5 g. ofcarbobenZoxy-L-phenylalanine (5 mmole) and 1.96 g. ofN-dichloroacetoxysuc- 'cinimide (7.5 mmole) in 3 ml. ofdimethylformamide.

1 1 After 2 hours, 0.07 ml. of water was added with stirring for fewminutes, further a mixed solution of glycine ethyl ester hydrochloride(5 mmole), 7 ml. of dimethylformamide and 0.7 ml. of triethylamine wasadded thereto and the mixture was stirred for further 2 hours.

After the reaction, 20 ml. of water was added and the mixture wasextracted with ethyl acetate. The ethyl acetate phase was separated,washed with a %-solution of sodium bicarbonate, and diluted withhydrochloric acid and water, then dried with anhydrous sodium sulfate,followed by condensation in vacuo to obtain the product as whitecrystals.

Yield: 1.55 g. (recovery: 81%). M.P.: Found: 108- 111 C. Reference:110-111 C. Optical rotation: Found: [a] =16.8 (c.=2.238, ethanol).Reference:

Elemental analysis.Found (percent): C, 66.30; H, 6.25; N, 7.33;Theoretical as based upon C H N O (percent): C, 65.73; H, 6.19; N, 7.28.

EXAMPLE 5 Carbobenzoxy-L-leucylglycine ethyl ester 2.28 ml. oftriethylamine were added dropwise with stirring to a cold mixture of2.65 g. of carbobenzoxy-L- leucine (10 mmole) and 3.39 g. ofN-dichloroacetoxysuccinimide mmole) in 3 ml. of dimethylformamide. Themixture was stirred for 3 hours, and then added with 0.14 ml. of chilledwater with continuous cooling and stirring. To this solution, a mixtureof 1.39 g. of glycine ethyl ester hydrochloride (10 mmole), 14 ml. ofdimethylformamide and 1.43 ml. of triethylamine was added. This reactionmixture was then stirred for further 3 hours. After adding chilledwater, the solution was extracted twice with ethyl acetate and theextract containing the product was washed with diluted hydrochloricacid, sodium bicarbonate solution and water successively, and dried overanhydrous sodium sulfate. After removal of the drying agent byfiltration, the ethyl acetate layer was evaporated at a reduced pressureso as to precipitate the product which was finally recrystallized fromethyl acetate/ petroleum ether.

Yield: 1.60 g (recovery: 55.1%). M.P.: 98-100 C. Optical rotation: [a]=-25.5 (c:2.08, ethanol).

Elemental analysis.Found (percent): C, 62.38; H, 7.88; N, 8.06.Theoretical as based upon C H N O (percent): C, 61.90; H, 7.45; N, 8.01.

EXAMPLE 6 Carbobenzoxy-L-phenylalanylglycine ethyl esterN-dichloroacetoxysuccinimide in Example 4 was replaced byN-monochloroacetoxysuccinimide to produce crystals ofoarbobenzoxy-L-phenylalanylglycine ethyl ester.

Yield: 34%. M.P.: 111 C. Optical rotation:

(c.=1.646, ethanol).

EXAMPLE 7 Benzylpenicillin procaine 0.4 ml. of triethylamine (3 mmole)was added to a cooled solution of 0.23 g. of N-phenylacetoxysuccinimide(1 mmole), prepared in accordance with the aforementioned Preparation 5,and 0.21 g. of 6-aminopenicillanic acid (1 mmole) in 3.6 ml. ofdimethylformamide. The solution was stirred for about 3 hours at roomtemperature, and then poured into ice water, adjusting the pH to 2 byaddition of 1 N-hydrochloric acid. This solution was extracted withmethyl isobutyl ketone and the methyl isobutyl ketone layer wasseparated. This extract was washed with 0.01 N-hydrochloric acid, thenextracted twice with 1 ml. of 1 molar sodium bicarbonate solution andonce with 0.5 ml. of the said solution. To the extracts combinedtogether containing the product, benxylpenicillin, there was added 0.27g. of procaine hydrochloride and cooled in an ice water bath, toprecipitate benzylpenicillin procaine as white crystals, which werewashed then with ethanol and diethyl ether, dried in vacuo, and found tocontain ,B-lactam group upon infrared analysis and to have an activityof 1000 units/ mg.

Yield: 400 mg. (recovery: 70%). M.P.: 124125 C. (dec.).

Elemental analysis.Found (percent): C. 59.22; H, 6.92; N, 9.90; S, 5.21.Theoretical as based upon (percent): C, 59.17; H, 6.85; N, 9.52; S,5.54.

EXAMPLE 8 Benzylpenicillin procaine 0.28 ml. of triethylamine was addeddropwise with stirring to a cold solution of 0.34 g. ofN-dichloroacetoxysuccinimide (1.5 mmole) and 0.136 g. of phenylaceticacid (1.0 mmole) in 3 ml. of dimethylformamide. The mixture was stirredfor about 2 hours in an ice water bath and then added with 0.04 ml. ofwater, followed by continuous agitation. Next, a solution of 0.15 g. of6-aminopenicillanic acid (0.7 mmole) in 0.28 ml. of triethylamine and1.5 ml. of dimethylformamide was added thereto. The mixture was stirredat room temperature for 3.5 hours. After adjusting the pH to 2.0 andpouring into ice water containing 3 mmole of hydrochloric acid, thesolution was extracted with methyl isobutyl ketone. The methyl isobutylketone layer was washed with diluted hydrochloric acid and extractedwith 1 mole of aqueous sodium bicarbonate solution. Adding 0.19 g. ofprocaine hydrochloride to this extract, the precipitated product formedby cooling was filtered, washed with water, ethanol and diethyl ether,respectively, dried and thus obtained crystals of benzylpenicillinprocaine. Recovery: 63%.

EXAMPLE 9 a-carbobenzoxyaminobenzylpenicillin dibenzylethylenediamine11.2 ml. of triethylamine (0.08 mole) were added dropwise to an ice-coldsolution of 13.6 g. of N-dichloroacetoxysuccinimide (0.06 mole) and 11.4g. of a-carbobenzoxyaminophenylacetic acid (0.04 mole) in 30 ml. ofdimethylformamide. The reaction continued for about 3.5 hours at roomtemperature, then the reaction mixture was extracted with 250 ml. ofethyl acetate and washed successively with water, 1 N-sodium bicarbonatesolution, 1 N-hydrochloric acid and water.

The ethyl acetate layer was dried with anhydrous sodium sulfate. Afterdrying agent was removed by filtration, the ethyl acetate layer wasevaporated under reduced pressure. The residue was dissolved in 30 ml.of dimethylformamide, followed by addition of 8.64 g. of6-aminopenicillanic acid (0.04 mole) and further by dropwise addition of16.8 ml. of triethylamine (0.12 mole) with cooling in ice. The resultingclear solution was allowed to warm up to room temperature and tocontinue the reaction for 2.5 hours, then adjusted the pH to 2 andextracted with 300 ml. of methyl isobutyl ketone. The extract was washedwith water, followed by adjusting of the pH to 7 by addition of 1N-sodium bicarbonate solution and of dropwise addition of 7.2 g. ofdibenzylethylenediamine diacetate in water. After precipitation theproduct was recovered by filtration, washed with water, dried overphosphorus pentoxide in vacuo to give, N,N'-dibenzylethylenediamine saltof a-carbobenzoxy aminobenzyl penicillin. M.P.: 127-158 C. (dec.).

Elemental analysis.Found (percent): C, 64.22; H, 6.07; N, 9.02.Theoretical as based upon 24 2s 3 s )2' 14 20 2 (percent): C, 63.68; H,5.80; N, 9.29.

1 3 EXAMPLE N,N'-dibenzylethylenediamine phenoxymethylpenicillin,N-phenoxyacetoxysuccinirnide (recovery: 60%).

Next, the reaction was continued under cooling for about 2.5 hourswithdropwise addition of 12.6 g. of triethylamine (0.09 mole) to asolution of 7.49 g. of N- phenoxyacetoxysuccinirnide (0.03 mole) and6.48 g. of 6-aminopenicillanic acid (0.03 mole) in 100 ml. ofdimethylformamide. The solution was adjusted to pH 2.0, extracted with150 ml. of methyl isobutyl ketone, and followed by extraction with 1N-sodium bicarbonate solution. The extract was adjusted to pH 7 andlyophilized. 10 g. of N,N-dibenzylethylenediamine diacetate solutionwere added to 11.7 g. of this lyophilized powder and filtered and theprecipitate was washed with water, dried in vacuo to giveN,N-dibenzylethylenediamine phenoxymethylpenicillin (recovery: 60%).M.P. 9597 C.

Elemental analysis.Found (percent): C, 59.01; H, 5.89; N, 8.25.Theoretical as based upon 1s 1a 2 5 )2' 1s 2o 2 (percent): C, 61.30; H,5.96; N, 8.95.

EXAMPLE 11 N,N-dibenzylethylenediamine phenoxyethylpenicillin In theprocess of Example 10, the phenoxyacetic acid was replaced byphenoxypropionic acid to produce N,N- dibenzylethylenediaminephenoxyethylpenicillin (recovery: 62.5%). M.P.: 93-100" C.

Elemental analysis.Found (percent): C, 60.61; H, 6.20; N, 8.28.Theoretical as based upon 17 2o 2 5 )z' 1s 2u 2 (percent): C, 60.83; H,6.19; N, 8.67.

EXAMPLE 12 N,N-dibenzylethylenediamine phenoxypropylpenicillin In anExample 10 the phenoxyacetic acid was replaced by phenoxybutyric acid toproduce N,N'-dibenzylethylenediamine phenoxypropylpenicillin (recovery:50.3%).

Elemental analysis.Found (percent): C, 63.10; H, 6.38; N, 8.82.Theoretical as based upon 1a 22 2 5 )2 1s '2o 2 v (percent): C, 62.63;H, 6.42; N, 8.43. 0

EXAMPLE 13 In the process of Example 10, the dichloroacetoxysuccinimideand phenoxyacetic'acid were replaced by monochloroacetoxysuccinimide andphenoxybutyric acid respectively to produce the same product as obtainedin Example 12. I

. EXAMPLE 14 N,N'-dibenzylethylenediamine-3- (o-chlorophenyl) -5methyl-4-isoxazolylpenicillin then at room temperature for 3 hours. Thesolution was extracted twice with total 300 ml. of ethyl acetate,subsequently washed with water, 1 N-sodium bicarbonate solution, 1 Nhydrochloric acid and water, respectively. The washed solution was driedover anhydrous sodium sulfate. p 1

After removal of the drying agent by filtration, the ethyl acetate layerwas evaporated in vacuo and the residue was dissolved in 25 ml. ofdimethylformamide, to which is added then 6.5 g. of 6-aminopenicillanicacid (0.03 mole) and 2.45 g. of Z-methylimidazole under cooling to reactwith each other for 3 hours. The reacted solution was allowed to standovernight at room temperature, adjusted to pH 2.0 in an ice water bathand extracted with ml. of diethyl ether. The ether solution was thenextracted with 30 ml. of 1 N-sodiu-m bicarbonate solution and 5.4 g. ofN,N-dibenzylethylenediamine diacetate in water was added thereto. Aftercooling oif the reaction mixture, the filtered precipitate was washedwith water and dried to obtain N,N' dibenzylethylenediamine-3-(o-chlorophenyl) -S-methylisoxazolylpenicillin.

Yield: 7.7 g. (recovery: 45%). M.P.: 5564 C.

Elemental aualysis.Found (percent): C, 58.25; H, 5.46; N, 9.55; Cl,6.34. Theoretical as based upon (C19H1gN305SCl)2C16H20N (PCI'CCIIL): C,H, 5.04; N, 10.08; Cl, 6.39.

EXAMPLE 15 N,N'-dibenzylethylenediamineu-methoxy-3,4-dichlorobenzylpenicillin In the process of Example 10, thephenoxyacetic acid was replaced by a-methoxy-3,4dichlorophenylaceticacid to produce N,N'-dibenzylethylenediamine a-methoxy-3-4-dichlorobenzylpenicillin. (Recovery: 45%.)

Elemental ana1ysis.Found (percent): C, 56.08; H, 5.23; N, 5.31; Cl,13.42. Theoretical as based upon (C1qH 3NO5SC12)2'C1 H2oN2 (percent): C,H, 5.19; N, 5.19; 01, 13.15.

EXAMPLE 16 N,N'-dibenzylethylenediamine 2-ethoxy-1-naphthylpenicillin Inthe process of Example 14, 3-(o-chlorophenyl)-5- methyl-4-isoxazolecarboxylic acid was replaced by 2- ethoxy-l-naphthoic acid to produceN,N'-di'benzylethylenediamine 2 ethoxy l-naphthylpenicillin. (Recovery:41.0%.)

Elemental analysis.-Found (percent): C, 66.38; H, 6.11 N, 6.66.Theoretical as based upon 21 22 2 5 2 is zo z (percent): C, 65.89; H,6.05; N, 6.81.

EXAMPLE 17 N,N'-dibenzylethylenediamine 6- (carbobenzoxyglycyl)aminopenicillanic acid In the process of Example 10, the phenoxyaceticacid was replaced by carbobenzoxyglycine to produceN,N-dibenzylethylenediamine 6 (carbobenzoxyglycyl)-aminopenicillanicacid. (Recovery: 70.7%.)

Elemental analysis.Found (percent): C, 58.34; H, 5.95; N, 10.87.Theoretical as based upon 1a 21 3 6 )2 16 2o 2 (percent): C, 59.19; H,5.88; N, 10.62.

EXAMPLE 18 N,N'-dibenzylethylenediamine6-(carbobenzoxyphenylalanyl)-aminopenicillanic acid In the process ofExample 10, phenoxyacetic acid was replaced by carbobenzoxyphenylalanineto produce N,N- dibenzylethylenediamine 6-(carbobenzoxyphenylalanyl)-aminopenicillanic acid. (Recovery: 72.3%.)

Elemental analysis-Found (percent): C, 64.69; H, 6.06; N, 9.00.Theoretical as based upon 25 27 3 6 2 C16H20N2 (percent): C, 64.17; H,5.99; N, 9.07.

EXAMPLE 19 N,N'-dibcnzylethylenediamine-6-(car bobenzoxyseryl)aminopenicillanic acid In the process of Example 10, the phenoxyaceticacid was replaced by carbobenzoxyserine to produceN,N'-dibenzylethylenediamine 6-(carbobenzoxyseryl)-aminopenicillanicacid. (Recovery: 60.7%.)

Elemental analysis-Found (percent): C, 57.71; H, 6.17; N, 9.93.Theoretical as based upon (percent): C, 58.05; H, 6.09; N, 10.03.

EXAMPLE 20 N,N'-dibenzylethylenediamine-6- carbobenzoxyalanyl)aminopenicillanic acid In the process of Example 10, the phenoxyaceticacid was replaced by carbobenzoxyalanine to produce N,N'-dibenzylethylenediamine 6-(carbobenzoxyalanyl)-aminopenicillanic acid.(Recovery: 75.8%.)

Elemental analysis.-Found (percent): C, 60.45; H, 6.01; N, 10.61.Theoretical as based upon 1s 23 a s )2 1e 2o 2 (percent): C, 59.87; H,6.09; N, 10.34.

EXAMPLE 21 N,N-dibenzylethylenediamine-6-myristoylaminopenicillanic acidIn the process of Example 10, the phenoxyacetic acid was replaced bymyristic acid to produceN,N'-dibenzylethylenediamine-6-myristoylaminopenicillanic acid.(Recovery: 55.4%.)

Elemental analysis.Found (percent): C, 65.88; H, 8.03; N, 7.59.Theoretical as based upon 22 as 2 4 2 rs zo z (percent): C, 66.53; H,7.94; N, 7.76.

EXAMPLE 22 N,N'-dibenzylethylenediamine-6-lauroy1aminopenicillanic acidIn the process of Example 10, the phenoxyacetic acid was replaced bylauric acid to produce N,N'-dibenzylethylenediamine-6-aminopenicillanicacid. (Recovery: 62.0%.) Elemental analysis.Found (percent): C, 65.33;H, 8.53; N, 7.94. Theoretical as based upon (CZOHSQNZOIS 2 C16H20N2(percent): C, 64.85; H, 8.49; N, 8.10.

EXAMPLE 23 N,N-dibenzylethylenediamine-6-caproylaminopenicillanic acidIn the process of Example 10, the phenoxyacetic acid was replaced bycaproic acid to produce N,N'-dibenzylethylenediamine-6caproylaminopenicillanic acid. (Recovery: 58.0%.)

Elemental analysis.Found (percent): C, 61.38; H, 7.44; N, 9.48.Theoretical as based upon (percent): C, 60.81; H, 7.37; N, 9.67.

We claim:

1. A process for the production of a compound having an acid amidelinkage, said compound having the general formula:

wherein R is a member selected from the group consisting of amonochloromethyl and a dichlorornethyl group, with a second compoundhaving the following general formula:

wherein R has the same meaning as hereinbefore described, wherein themolar ratio of said first compound to said second compound is from about1.4 to about 2 moles of said first compound per 1 mole of said secondcompound, said reaction being conducted in the presence of from about1.5 to about 2.1 moles of a tertiary organic amine per 1 mole of saidsecond compound to yield a succinimide ester compound having the generalformula wherein R has the meaning hereinbefore described; andsubsequently reacting said succinimide compound with an amino compoundin a ratio of from 1 to 2 moles of said succinimide compound per 1 moleof said amino compound, said amino compound being represented by thefollowing general formula:

said reaction being conducted in the presence of from 1 to 3 moles of atertiary organic amine per 1 mole of said amino compound wherein R hasthe same meaning hereinbefore described in said inert organic solvent ata temperature of from about 0 C. to room temperature to thereby yieldthe desired product expressed by said initial formula.

References Cited UNITED STATES PATENTS 8/1950 Magat 26078 5/1967Anderson 260326.3

OTHER REFERENCES Wolman, Israel, J. Chem., 5, 231236 (1967). Sakakibaraet al. I, Bull. Chem. Soc. Jap., 37, 1231- Sakakibara et a1. II, Bull.Chem. Soc. Jap., 38, 1979 1984 (1965).

LEWIS GOTTS, Primary Examiner M. KASSENOFF, Assistant Examiner U.S. Cl.X.R.

